Alport syndrome Genetics

Alport syndrome is caused by mutations in the type IV collagen genes. Type IV collagen is a family of six proteins, or chains, that are known as alpha-1 through alpha-6. Mutations that affect the alpha-3, alpha-4, and alpha — 5 chains cause Alport syndrome. The 3 genetic types of Alport syndrome are:

  • XLAS (X-linked Alport syndrome) — The most common form that accounts for 80% to 85% of the cases and results from mutations of the alpha-5 chain type IV collagen (gene COL4A5)
  • ARAS (autosomal recessive Alport syndrome) — This form accounts for 15% of the cases and is caused by mutations in the alpha-3 or alpha-4 chains (genes COL4A3 or COL4A4)
  • ADAS (autosomal dominant Alport syndrome) — Rare form that accounts for about 5% of the cases and is caused by mutations in the alpha-3 or alpha-4 chains (genes COL4A3 or COL4A4).

X-Linked Alport syndrome (XLAS)

Males have one X and one Y chromosome and females have two X chromosomes. X-linked Alport syndrome is caused by mutations in the COL4A5 gene, which resides on the X chromosome. X-linked disorders cause more severe symptoms in affected males than in affected females because males have only one X chromosome.

Males with XLAS are severely affected and always develop kidney failure sometime in their lives, because they do not have a normal copy of the gene to buffer the effect of the mutant gene. Females, who have two X chromosomes, have two copies of the COL4A5 gene. In girls with XLAS, one copy of the gene carries a mutation, but the other copy is normal. The normal copy of the gene counters the effect of the mutation, so that girls with XLAS usually have milder symptoms than boys. However, girls with X-linked Alport syndrome can also develop kidney failure and should not be considered as only carriers of XLAS.

A male with XLAS will pass the affected X chromosome gene to all of his daughters and they will have XLAS. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female with XLAS has a 50% chance with each pregnancy of having an affected child.

Approximately 10 – 15% of XLAS mutations occur randomly (spontaneously), where neither parent carries a mutation.


Autosomal Recessive Alport syndrome (ARAS)

Autosomal recessive disorders result when both copies of a gene are defective. Typically, each parent of a child with a recessive condition passes a mutant gene to the affected child. The genes COL4A3 and COL4A4 are located on chromosome 2. Each person has two copies of this chromosome, and two copies of both the COL4A3 and COL4A4 genes. The parents only have one mutation in one of the chromosomes and so they can have no symptoms or have some hematuria (blood in the urine). However, they will not have progression of the disease.

When each parent carries a mutation in COL4A3 or COL4A4, there is a 25% chance with every pregnancy that the child will have ARAS. Unlike X-linked Alport syndrome, the autosomal recessive type affects females just as severely as males.

Autosomal Dominant Alport syndrome (ADAS)

About 5% of people with Alport syndrome have ADAS. These people have one mutant copy of the COL4A3 or COL4A4 gene. Mutation in one copy of COL4A3 or COL4A4 can cause progressive kidney disease and hearing loss. People with ADAS resemble people with XLAS, with some differences: kidney failure occurs relatively late in life (after age 40), changes in the eyes are very unusual and there is no difference in severity of disease in males and females. People with ADAS usually have a family history that is positive for progressive kidney disease and hearing loss. Mutation in one copy of COL4A3 or COL4A4 can also cause thin basement membrane nephropathy (TBMN), which differs from ADAS in that progressive kidney disease and hearing loss are very unusual. People with TBMN usually have a family history that is negative for progressive kidney disease and hearing loss. Researchers are still trying to understand why some people with these mutations have ADAS and others have TBMN.

Each child of an affected parent has a 50% chance of inheriting the mutation.

Genetic testing, including prenatal testing is available. It is recommended you speak with your nephrologist and/or genetic counselor if you are interested in having these tests done. See Genetic Testing Labs for more information on testing.

References that were used to compile this discussion include: Clifford E. Kashtan, MD – Alport syndrome and Thin Basement Membrane Nephropathy; Alport syndrome Treatments and Outcomes Registry (ASTOR); National Organization of Rare Diseases, Alport syndrome

You can find additional information about Alport syndrome genetics on the ASF Blog.

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